Discovery of BMS-641988, a Novel Androgen ... - ACS Publications

Subscriber access provided by UNIV OF MISSISSIPPI

Letter

The Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer Aaron Balog, Richard Rampulla, Gregory Martin, Stanley Krystek, Ricardo Attar, Janet DellJohn, John D DiMarco, David Fairfax, Jack Z Gougoutas, Christian Holst, Andrew Nation, Cheryl Rizzo, Lana Rossiter, Liang Schweizer, Weifang Shan, Steven H. Spergel, Thomas Spires, Georgia Cornelius, Marco Gottardis, George L Trainor, Gregory D. Vite, and Mark Salvati ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.5b00173 • Publication Date (Web): 19 Jun 2015 Downloaded from http://pubs.acs.org on June 22, 2015

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

ACS Medicinal Chemistry Letters is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 6

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Medicinal Chemistry Letters

The Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer §

§

Aaron Balog *, Richard Rampulla , Gregory S. § § Martin♯, Stanley R. Krystek , Ricardo Attar , Janet § § Dell-John , John D. DiMarco , David Fairfax♯, Jack § § Gougoutas , Christian L. Holst♯, Andrew Nation , § § Cheryl Rizzo , Lana M. Rossiter♯, Liang Schweizer , § § § Weifang Shan , Steven Spergel , Thomas Spires , § § Georgia Cornelius , Marco Gottardis , George § § § Trainor , Gregory D. Vite and Mark E. Salvati §

4

enzalutamide via AR mutations. Thus, there is a need for novel antiandrogens with distinct interactions in the AR ligand binding domain that could be dosed together or sequentially in the clinic to combat the potential pathways leading to CRPC progression. Our laboratory has been focused on the rational strucutral-based design of structurally novel, non-steroidal small molecule AR antagonists for the potential treatment of CRPC. Figure 1. Known androgen receptor antagonists.

Bristol Myers-Squibb Research and Development, P. O. Box 4000, Princeton, NJ 08543 ♯

Albany Molecular Research Inc., 21 Corporate Circle, Albany, NY 12203

RECEIVED DATE (will be automatically inserted after manuscript is accepted). Abstract: BMS-641988 (23) is a novel, non-steroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.

Carcinoma of the prostate (CaP) is the most nd common malignancy among men in the US and the 2 most common cause of cancer-related death worldwide 1 after lung cancer. The androgen receptor (AR) is a member of the nuclear hormone superfamily of ligand-induced transcription factors and is a key signaling pathway leading to the emergence of CaP. Androgen ablation, by surgical or chemical castration in combination with an antiandrogen such as hydroxyflutamide (1) or bicalutamide (2), has been the 2 standard of care for advanced CaP for many years. This therapy is initially effective in 80-90% of patients, however >50% of the patients will ultimately develop castration resistant prostate cancer (CRPC) 3 The treatment of CRPC is after ~18 months. challenging due to the sustained AR signaling, which is the result of AR overexpression/activation and the 4 presence of activating AR mutations. Furthermore, it has been reported that CRPC tumors express the necessary cytochrome P450 enzymes for intratumoral androgen production, thus by-passing the effects of chemical castration which targets only gonadal 5 androgen production. These findings suggest that CRPC remains AR dependent and effective therapies must target AR signaling directly with improved nextgeneration AR antagonists. MDV3100 (enzalutamide, 3) is a potent AR antagonist that was recently approved by the US Food and Drug Administration for the treatment of metastatic CRPC patients that have progressed post 6 treatment with docetaxel. Although enzalutamide has shown promise in treating these patients, nearly all pateints go on to develop resistance to

Previously, we have reported a series of [2.2.1] 7 8 carbobicyclic and oxabicyclic succinimide based AR antagonists (4 and 5, Figure 1). These compounds demonstrated potent binding affinity (Ki) and functional antagonist activity (IC50) against the wildtype AR as found in the MDA-MB-453 cell-line (Table 1). These compounds compared favorably in terms of potency to the clinically used antiandrogens hydroxyflutamide (1) and bicalutamide (2). We designed a series of oxabicyclic-based AR antagonists, such as 5, that demonstrated a superior pharmacokinetic (PK) profile compared to the carbocycles such as 4. Based on our understanding of the need for sustained AR supression in an effective AR antagonist, we expected that robust PK would be 8 essential for an efficacious AR antagonist. Accordingly, compound 5 was shown to be efficacious in the CWR22-BMSLD1 human prostate cancer xenograft model, where bicalutamide shows only 8 We looked to incorporate PK limited efficacy. properties critical for an effective AR antagonist, such as log T1/2, with a broader activity profile than is seen with 1st generation agents such as bicalutamide. Accordingly, we screened out agents against the human CaP model CWR22, which has been shown to be refractory to both bicalutamide and hydroxyflutamide. Based on this result, we wanted to expand the scope of this series by using a structurebased approach to identify even more potent AR antagonists. Utilizing available X-ray co-crystal structures of the AR generated at BMS, we developed a molecular model of the WT AR LBD (Figure 2) to aid in the 9,10 indentification of new AR antagonists. In this model, interactions of N-705 with both the C-5 hydroxyl and the bridging oxygen of compound 5 are evident. Additional interactions between R752 and Q711 and the aryl nitrile functionality of compound 5 are also present. We postulated that endosubstitution at C-5 or C-6 of the bicycle would result in a direct interaction with helix-12 (H-12), possibly creating a more classical AR antagonist conformation, similar to that predicted for bicalutamide. The key

ACS Paragon Plus Environment

1


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

hydrogen bonding interaction with N-705 would be maintained by the bridging oxygen as seen with bicalutamide (2) which is shown in orange. Thus, we set out to investigate the effect of various substitutions on the endo-face of [2.2.1]-oxabicyclic core of compound 5.

Page 2 of 6

ester of 2,5-dimethyl-3-furoic acid occurred at 120 °C to give only the desired exo-isomer 9 after precipitation. Catalytic hydrogenation led to formation of the endo-ester by selective reduction from the beta-face of the olefin. Normal-phase chiral HPLC separation of the racemic endo-ester gave the desired enantiomer 10 in 45% yield and >99% ee. The optical isomer depicted by compound 10 was determined to be optimal for potent AR antagonist activity and the absolute and relative stereochemistry was eventually confirmed by X-ray crystallographic 12 analysis of compound 23. Treatment of 10 with 3N HCl gave the key intermediate acid 11 in good yield. Compounds 12 and 13 were prepared by standard ester and amide formation conditions. The acid 11 was found to have poor potency in our cellular in vitro assays (Table 1), but the ester 12 and amide 13 had promising binding and functional antagonist activity in the MDA-MB-453 cell-line. Unfortunately, neither the amide nor the ester had potency that was superior to the exo-hydroxy analog 5, so we investigated additional functionalities on the oxabicycle in an effort to find highly potent AR antagonists. The endo-amine 14 could be prepared from the acid 11 by sequential Curtius 13 rearrangement and subsequent TFA-promoted cleavage of the resulting Teoc-carbamate in 77% yield. Compound 14 had only modest affinity to the AR, but offered a good handle with which to further functionalize the oxa-bicyclic core.

Figure 2. Compound 5 docked into a model of the wild-type AR ligand binding domain.

Our efforts started with the synthesis of compounds 11-13 by the synthetic route shown in Scheme 1. Maleimide 8 was prepared from the aniline 6 and 11 maleic anhydride (7) under standard conditions. Diels-Alder cycloaddition between 8 and the MEM Scheme 1. Synthetic route to endo-substituted bicycles NH2

O F 3C O

CN 6

7

H3C

O

O

a

H O

b N

CN

O

CF 3

O MEMO2C

N

H O CH 3

8

H 3C

CF 3

c,d

CN

H O

O MEMO2C 10

9

CF 3

N

H O CH3

CN

>99% ee

e H3C O

R O

H O

H3C

CF 3

N

f or g

CN

O HO2C

H O CH3

COEt H 3C SO2NHCH 3 H O CONHi-Pr CO2(N-CH 3-Piperdine) O N R SO2Me N H H SO2P h O CH 3 SO2(2 -F-Ph) SO2-3 -pyridine SO2E t

N

CF 3 CN

H O

CH 3

12 , R = Oi-Pr 13 , R = NCH3Ph 15 16 17 18 19 20 21 22 23

H O

11

H3C

CF3 conditions

O

CN H 2N

H O

CF3

N

H O CH 3

h,i

CN

14

a) HOAc, 110 °C, 88%; b) MEM 2,5-dimethyl-3-furoate, 120 °C, 33%, exo-isomer only; c) H2, Pd/C, EtOAc, 1 atm, 50%; d) Chiral HPLC separation, 45%, >99% ee; e) 3 N HCl, THF, 22 °C, 98%; f) (COCl)2, DCM then i-PrOH, TEA, 97%; g) EDC, HOBt, DIEA, N-methylaniline, DMF, 88%; h) 2-trimethylsilylethanol, DPPA, TEA, 4Å MS, 1,4-dioxane, 75 °C, 78%; i) TFA, CH2Cl2, 22 °C, 99%;

A series of amides, sulfamides, carbamates, ureas and sulfonamides was prepared from the amine 14 in library format. Standard coupling techniques were utilized to prepare analogs 15-23 (see Supporting Information); the corresponding in vitro biological

data is shown in Table 1. In general, these analogs were potent binders to, and functional antagonists of, the wild-type AR present in the MDA-MB-453 cell line. The amide 15 and the carbamate 18 had excellent potency in vitro, while the sulfamide 16 and


2

Page 3 of 6

urea 17 were weakly active. The sulfonamides 19-23 had the best overall in vitro profile, with robust affinity and potent antagonist activity, superior to that for bicalutamide (2). We next wanted to investigate the pharmacodynamic effects of these novel AR antagonists in vivo. Compounds 13-23 were progressed into the immature rat prostate weight (IRPW) PK/PD model, where the compound effect on AR dependent growth of the prostate and seminal 14 vesicles was measured (Table 2). In this model, compounds were dosed orally once a day at 1 or 10 mg/kg for 4 days with plasma concentrations of drug measured 2 hours post-dose on day 4. Agents that effectively block the proliferative effect of the AR in these tissues would result in a decrease in the total weight of organs relative to a control group. As expected, the amide 13 had poor pharmacodynamic effect in this model, most likely due to modest functional antagonist potency. The amide 15 and the urea 17 gave only modest PD effects even with very high exposure after 1 and 10 mg/kg doses. This result correlated with the very high serum protein binding measured for these two compounds (>99% in mouse serum). The sulfonamide 16 and the carbamate 18 also had only modest PD effects, but this was most likely due to poor exposure relative to compound 2. The sulfonamide series stood out in the IRPW model by having excellent PD with modest exposure, suggesting superior in vivo potency compared to the ureas, amides, carbamates and sulfamides. Compounds 19-23 all demonstrated robust PD at a 10 mg/kg dose with exposures significantly less than observed for bicalutamide. Of these promising analogs, the ethyl sulfonamide 23 was chosen for further studies due to robust potency in vivo and a promising PK profile in rats.

is very weak (>40 µM) and there is very low potential for CYP induction based on the human PXR transactivation assay. Plasma protein-binding of 23 was measured by equilibrium dialysis and very low levels of plasma protein binding were observed in all species (>10% free). Compound 23 demonstrated excellent metabolic stability in hepatocyte incubations and the predicted clearance in all species is low, especially for human. Finally, the PK properties of compound 23 were assessed in mouse, rat and dog following both oral and IV doses. Consistent with the predicted hepatic clearance, compound 23 demonstrated moderate to long half-lives and very low clearance across species. Table 2. Immature rat prostate weight assay results IRPW 10 mg/kg SV/FBa 41 ± 4 43 ± 8.0 89 ± 8.1 34 ± 6.0 36 ± 4.2 56 ± 8.9

2 13 14 15 16 17

IRPW 1 mg/kg SV/FBa 69 ± 24 88 ± 19 89 ± 22 87 ± 39 89 ± 5.9 115 ± 3.9

18

105 ± 24

87 ± 16

19 20 21 22 23

64 ± 13 63 ± 14 56 ± 6.5 44 ± 8.6 58 ± 13

26 ± 4.2 31 ± 5.2 24 ± 1.8 23 ± 11 26 ± 3.0

#

Exposure 1 mg/kg (µ µM)b

Exposure 10 mg/kg (µ µM)b

2.3 ± 0.4 1.8 ± 0.68 0.08 ± 0.02 24 ± 1.7 0.01 ± 0.001 8.3 ± 0.4 0.012 ± 0.004 0.29 ± 0.07 0.23 ± 0.03 0.16 ± 0.02 0.05 ± 0.01 0.79 ± 0.17

9.5 ± 1.4 12.0 ± 0.82 0.48 ± 0.32 190 ± 73 0.23 ± 0.08 60 ± 6.1 0.076 ± 0.017 4.0 ± 1.2 2.4 ± 0.52 1.9 ± 0.06 0.52 ± 0.09 4.0 ± 0.42

SV/FB is the percentage of weight of the seminal vesicles over the full body weight of the rat (n=3) where testosterone treated control = 100% and sham = 10%. b Plasma exposure measured 2 hours post-dose on day 4.

a

Figure 3. In vivo efficacy of compound 23 in the CWR22BMSLD1 prostate cancer xenograft model.

Table 1. In vitro biological activity # 2

MDA-MB-453 Ki (nM)a 64

MDA-MB453 IC50 (nM)b 173

5

8

10

2000

11 1600 >5000 12 23 22 13 50 34 14 31 60 15 3.0 23 16 50 34 17 31 60 18 7.0 6 19 12 20 20 10 1.0 21 1.0 10 22 2.0 7.0 23 1.7 16 a Binding (Ki) determined through direct displacement with 3 [ H]-DHT in the MDA-MB-453 cell-line b Functional antagonist activity (IC50) in the MDA-MB-453 cell-line determined through a transiently transfected reporter system utilizing the secreted alkaline phosphatase reporter gene driven by the AR-dependent PSA promoter.

Compound 23 was further profiled to determine in vitro safety and ADME properties (Table 3). Inhibition of human cytochrome P450 (CYP) isoforms

Median Tumor Growth (mm3)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1500

Vehicle

Therapy Switched to BMS-641988

1000

Bicalutamide, 150 mg/kg BMS-641988, 90 mg/kg Bicalutamide, 150 mg/kg BMS-641988, 90 mg/kg

500

0 15

25

35

45

55

65

75

Days post Implant

Compound 23 was then tested in the human prostate cancer xenograft model CWR22-BMSLD1 15 (Figure 3). Treatment with bicalutamide (2) (150 mg/kg, po, qd x 35 days) resulted in good tumor growth inhibition for the initial 10 days, followed by regrowth of the tumor at a rate that was similar to control. When compound 23 was dosed (90 mg/kg, po, qd x 45 days) excellent tumor growth inhibition was observed over the entire dosing period, demonstrating superior efficacy to bicalutamide (2). Additionally, we investigated the possibility of treating bicalutamide


3


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

resistant tumors in this model by allowing the bicalutamide-treated tumors to triple in size followed by a switch to treatment with compound 23. As shown in Figure 3, tumor growth continued for ~10 days after switching to compound 23, followed by nearly complete tumor growth inhibition for the remainder of dosing period. We were encouraged by this result as it gave strong evidence that compound 23 has the potential to treat forms of prostate cancer resistant to bicalutamide (2). Figure 4. Compound 23 docked into a model of the WT AR ligand binding domain.

Table 3. Summary of androgen receptor biological data and ADME properties for compound 23 Assay WT AR binding (Ki) MDA 453 (IC50) LNCaP (IC50) human CYP 1A2, 2B6, 2C8, 2C9, 2D6, 3A4) IC50 PXR-TA EC50 hERG inhibition @ 30 µM Protein binding (% free): mouse, rat, dog, human Rate of metabolism in hepatocytes: mouse, rat, dog, monkey, human 6 (pmol/min/10 cells) Predicted clearance: mouse, rat, dog, monkey, human (mL/min/kg) IV / PO PK: T1/2 (h), CL (mL/min/kg), AUC0-∞ (µM*h), %F

Results 1.7 ± 0.56 nM 16 ± 3 nM 153 ± 77 nM

Mouse (5 / 10 mg/kg):

2.4, 4.5, 39.1/74.1, 94.7

Rat (5 / 10 mg/kg):

3.7, 6.5, 31.7/40.5, 63.9

Dog (1 / 2 mg/kg):

21.8, 0.35, 102.1/160.2,79

a

Docking compound 23 into the wild-type AR ligand 10 binding domain (Figure 4) revealed the H-bond from N-705 to the bridging oxygen is likely intact as observed for compound 5. To accommodate the endosulfonamide at C-5, F876 must reorient resulting in a positional shift of Helix-11. This significant shift of Helix-11 results in a change in the overall architecture of the LBD, potentially giving compound 23 the promising antagonist profile presented here. Further profiling of compound 23 demonstrated an acceptable preclinical safety profile both in vitro and in vivo. This compound was selected for clinical development and advanced into phase I clinical 15,16 trials. In summary, we have utilized structure-based design to identify a new series of amino [2.2.1]oxabicyclosuccinimide AR antagonists. Lead molecules demonstrated potent antagonist activity in cellular binding and transactivation assays in vitro and had robust PK/PD profiles in the IRPW model. Compound 23 was shown to be superior to bicalutamide in the CWR22-BMSLD1 human CaP tumor xenograft model, and has the potential to address acquired bicalutamide resistance based on the results from these studies.

Page 4 of 6

> 40 µM > 50 μM 0% 14.8, 10.6, 16.5, 10.4 0, 26, 3.0, 1.0, 2.0 0, 16, 1.8, 0.6, 0.8

IC50 values are an average of three experiments.

ACKNOWLEDGMENT The authors thank Linda Fleming and the Department of Discovery Synthesis at Bristol-Myers Squibb for preparation of key intermediates. We also acknowledge the Departments of Lead Discovery & Optimization and Discovery Analytical Sciences for ADME and compound characterization support. Supporting Information Available: Synthetic procedures and characterization data for compounds 9-23 and biological methods. This material is available free of charge via the Internet at http://pubs.acs.org. References (1) Ghafoor, A.; Jemal, A.; Thomas, H.; Murray, T. and Thun, M. Cancer statistics for African Americans. Cancer J. Clin. 2002, 52, 322-325. (2) Crawford, E. D.; DeAntonio, E. P. Current status of combined androgen blockade: optimal therapy for advanced prostate cancer. J. Clin. Endocrinol. Metab. 1995, 80, 1062. (3) Dalesio, O. Maximum androgen blockade in advanced prostate cancer: an overview of the randomized trials. Lancet, 2000, 355, 1491-1498. (4) Scher, H.; Sawyers, C. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen receptor signaling axis. J. Clin. Oncol. 2005, 23, 8253. (5) Locke, J. A.; Guns, E. S.; Lubik, A. A.; Adomat, H. A.; Hendy, S. C.; Wood, C. A.; Ettinger, S. L.; Gleave, M. E.; Nelson, C. C. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008, 68(15), 6407-6415. (6) Ning, Y. M.; Pierce, W.; Maher, V. E.; Karuri, S.; Tang, S. H.; Chiu, H.-J.; Palmby, T.; Zirkelback, J. F.; Marathe, D.; Mehrotra, N.; Liu, Q.; Ghosh, D.; Cottrell, C. L.; Leighton, J.; Sridhara, R.; Ibrahim, A.; Justice, R.; Pazdur, R. Enzalutamide for treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel; United States Food and Drug Administration approval summary. Clin Cancer Res. 2013, 19(22), 6067 - 6073. (7) Salvati, M.; Balog, A.; Wei, D.; Pickering, D.; Attar, R.; Geng, J.; Rizzo, C.; Hunt, J.; Weinmann, R. and Martinez, R. Identification of a novel class of androgen receptor antagonists based on the bicyclic-1H-isoindole-1,3(2H)dione nucleus. Bioorg. Med. Chem. Lett. 2005, 15, 389. (8) Salvati, M.; Balog, A.; Shan, W.; Rampulla, R.; Giese, S.; Mitt, T.; Furch, J.; Vite, G.; Attar, R.; J.-K., Maria; Geng, J.; Rizzo, C.; Gottardis, M.; Krystek, S.; Gougoutas, J.; Galella, M.; Obermeier, M.; Fura, A. and Chandrasens, G. Identification and optimization of a novel series of [2.2.1]-oxabicyclo imidebased androgen receptor antagonists. Bioorg. Med. Chem. Lett. 2008, 18, 1910–1915. (9) Sack, J. S.; Kish, K.; Wang, C.; Attar, R.; Kiefer, S. E.; Yongmi, W.; Ginger, Y.; Scheffler, J. E.; Salvati, M. E.; Krystek, S. R.; Weinmann, R. and Einspahr, H. R. Crystallographic structures of the ligand-binding domains of


4

Page 5 of 6

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the androgen receptor and its T877A mutant complexed with the natural ligand dihydrotestosterone. Proc. Natl. Acad. Sci. 2001, 98, 4904. (10) Molecular modeling was performed using ICM software (Molsoft LLC, San Diego, CA). The docking of the ligands into WT AR LBD was carried out using the ICM docking procedure which is a two step process. Initial docking of ligands were carried out using grid potential representation of the receptor and flexible ligand. Five grid potentials describe the shape, hydrophobicity, electrostatics, and hydrogen bonding potential of the receptor. The conformations from the grid were then optimized with a full atom representation of the receptor and flexible ligand, by an ICM stochastic global optimization algorithm as implemented in version 2.7 of the Molsoft ICM program (Refs. a and b). (a) Molsoft (1998) ICM 2.7 Program Manual (Molsoft, San Diego, CA). (b) M. Totrov and R. Abagyan, Proteins Suppl. 1 (1997), p. 215. (11) Salvati, M.E.; Balog, A.; Pickering, D.A.; Giese, S.; Fura, A.; Li, W.; Patel, R.; Hanson, R.L.; Mitt, T.; Roberge, J.; Corte, J.R.; Spergel, S.H.; Rampulla, R.A.; Misra, r.; Xiao, H.-Y. Preparation of fused succinimides as modulators of nuclear hormone function. WO 20040077605. (12) The absolute and relative stereochemistry of compound 23 was confirmed by single-crystal x-ray crystallography. The coordinates have been deposited in the Cambridge Crystallographic Data Center, #779603. (13) Smith, P. A. S. Curtius reaction. Org. React. 1946, 3, 337. (14) Hershberger, L.G.; Shipley, E.G.; Meyer, R.K. Myotrophic activity of 19nortestosterone and other steroids determined by modified levator ani muscle method. Proc. Soc. Exp. Biol. Med. 1953, 83, 175. (15) Attar, R. M. ; Kunkel, M. J.; Balog, A.; Cvijic, M. E.; Dell-John, J.; Rizzo, C. A.; Schweizer, L.; Spires, T. E.; Platero, J. S.; Obermeier, M.; Shan, W.; Salvati, M. E.; Foster, W. R.; Dinchuk, J.; Chen, S.-J.; Vite, G.; Kramer, R.; Gottardis, M. Discovery of BMS-641988, a novel and potent inhibitor of androgen receptor signaling for the treatment of prostate cancer. Cancer Res. 2009, 69, 6522- 6529. (16) Rathkopf, D.; Liu, G.; Carducci, M. A.; Eisenberger, M. A.; Anand, A.; Morris, M. J.; Slovin, S. F.; Sasaki, Y.; Takahashi, S.; Ozono, S.; Fung, N. K. E.; Cheng, S.; Gan, J.; Gottardis, M.; Obermeier, M. T.; Reddy, J.; Zhang, S.;

Vakkalagadda, B. J.; Alland, L.; Wliding, G.; Scher, H. I. Phase I doseescalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer. Clinc. Cancer Res. 2010, 17(4), 880-887.


5


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 6

For Table of Contents use only.

The Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer

Aaron Balog§*, Richard Rampulla§, Gregory S. Martin♯, Stanley R. Krystek§, Ricardo Attar§, Janet DellJohn§, John D. DiMarco§, David Fairfax♯, Jack Gougoutas§, Christian L. Holst♯, Andrew Nation§, Cheryl Rizzo§, Lana M. Rossiter♯, Liang Schweizer§, Weifang Shan§, Steven Spergel§, Thomas Spires§, Georgia Cornelius§, Marco Gottardis§, George Trainor§, Gregory D. Vite§ and Mark E. Salvati§

Table of Contents Graphic H3C

H3C

O O S N H

O

H O N

CF3 CN

H O CH3

23 . MDA MB 453 Ki = 1 7 nM


Discovery of BMS-641988, a Novel Androgen ... - ACS Publications

Recommend Documents